title: Extracellular signal-regulated kinase (ERK) phosphorylates histone deacetylase 6 (HDAC6) at serine 1035 to stimulate cell migration.
abstract: Histone deacetylase 6 (HDAC6) is well known for its ability to promote cell migration through deacetylation of its cytoplasmic substrates such as α-tubulin. However, how HDAC6 itself is regulated to control cell motility remains elusive. Previous studies have shown that one third of extracellular signal-regulated kinase (ERK) is associated with the microtubule cytoskeleton in cells. Yet, no connection between HDAC6 and ERK has been discovered. Here, for the first time, we reveal that ERK binds to and phosphorylates HDAC6 to promote cell migration via deacetylation of α-tubulin. We have identified two novel ERK-mediated phosphorylation sites: threonine 1031 and serine 1035 in HDAC6. Both sites were phosphorylated by ERK1 in vitro, whereas Ser-1035 was phosphorylated in response to the activation of EGFR-Ras-Raf-MEK-ERK signaling pathway in vivo. HDAC6-null mouse embryonic fibroblasts rescued by the nonphosphorylation mimicking mutant displayed significantly reduced cell migration compared with those rescued by the wild type. Consistently, the nonphosphorylation mimicking mutant exerted lower tubulin deacetylase activity in vivo compared with the wild type. These data indicate that ERK/HDAC6-mediated cell motility is through deacetylation of α-tubulin. Overall, our results suggest that HDAC6-mediated cell migration could be governed by EGFR-Ras-Raf-MEK-ERK signaling.
authors.affiliation: From the Department of Pathology and Cell Biology, University of South Florida Morsani College of Medicine, Tampa, Florida 33612.
authors.forename: Kendra A
authors.initials: KA
authors.lastname: Williams
authors.forename: Mu
authors.initials: M
authors.lastname: Zhang
authors.forename: Shengyan
authors.initials: S
authors.lastname: Xiang
authors.forename: Chen
authors.initials: C
authors.lastname: Hu
authors.forename: Jheng-Yu
authors.initials: JY
authors.lastname: Wu
authors.forename: Shengping
authors.initials: S
authors.lastname: Zhang
authors.forename: Meagan
authors.initials: M
authors.lastname: Ryan
authors.forename: Adrienne D
authors.initials: AD
authors.lastname: Cox
authors.forename: Channing J
authors.initials: CJ
authors.lastname: Der
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.forename: John
authors.initials: J
authors.lastname: Koomen
authors.forename: Eric
authors.initials: E
authors.lastname: Haura
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Santo V
authors.initials: SV
authors.lastname: Nicosia
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthias
authors.forename: Chuangui
authors.initials: C
authors.lastname: Wang
authors.forename: Wenlong
authors.initials: W
authors.lastname: Bai
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000107:Acetylation; D000818:Animals; D016466:CHO Cells; D002465:Cell Movement / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*
chemical_list: D014404:Tubulin; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D048052:Mitogen-Activated Protein Kinase 3; C433811:HDAC6 protein, human; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Cell Migration; ERK; Histone Deacetylase; MAP Kinases (MAPKs); Protein Phosphorylation